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    Home > Active Ingredient News > Endocrine System > Rare cases beware of "non-classical congenital adrenal hyperplasia" hidden in common diseases: 1 case of cytochrome P450 oxidoreductase deficiency (PORD)

    Rare cases beware of "non-classical congenital adrenal hyperplasia" hidden in common diseases: 1 case of cytochrome P450 oxidoreductase deficiency (PORD)

    • Last Update: 2021-11-14
    • Source: Internet
    • Author: User
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    Congenital adrenal hyperplasia (CAH) is a group of rare autosomal recessive inherited diseases
    .

    On May 11, 2018, the National Health Commission and five departments jointly issued China's "First Batch of Rare Diseases Catalog".
    The most common type of CAH, 21-OHD (21-OHD), was included and listed.
    The first among 121 rare diseases
    .

    The pathogenesis of CAH The main pathogenesis of CAH lies in the congenital defects of various catalytic enzymes in the process of adrenal corticosteroid hormone biosynthesis, leading to insufficient adrenal cortex hormone synthesis, and feedback regulation via the hypothalamic-pituitary-adrenal axis (HPA axis) , Increase the secretion of corticotropin releasing hormone (CRH) and corticotropin (ACTH), leading to adrenal hyperplasia and various metabolic disorders of the body
    .

    Under normal circumstances, CRH secreted by the hypothalamus and ACTH secreted by the pituitary gland can promote the proliferation of adrenal cortex cells and increase hormone synthesis and secretion.
    When the peripheral blood cortisol reaches a certain concentration, the secretion of CRH and ACTH can be reduced through a feedback mechanism.
    The physiological balance of adrenal cortex hormones
    .

    If any enzyme in the hormone synthesis pathway is defective, the blood cortisol concentration will be reduced, and the negative feedback regulation of the HPA axis will increase the secretion of ACTH from the pituitary and stimulate the adrenal cortex hyperplasia
    .

    Defects of specific enzymes can lead to reduced production of downstream hormones (such as 11-deoxycorticosterone, cortisol, testosterone, estradiol), and accumulation of upstream intermediate metabolites (such as progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone) Ketone, 11-deoxycorticosterone), and can be compensated by the bypass metabolic pathway, resulting in excessive production of bypass metabolites (such as 11-deoxycorticosterone, dehydroepiandrosterone, androstenedione, testosterone)
    .

    CAH includes many types: 21-hydroxylase deficiency (21-OHD, about 90%-95% of CAH), 11β-hydroxylase deficiency (11β-OHD, 5%-8%), 3β- Hydroxysteroid dehydrogenase 2 deficiency (3β-HSD2, about 1%), 17α-hydroxylase/17,20 lyase deficiency (CYP17A1, <1%), cytochrome P450 oxidoreductase deficiency (PORD, rare), lipoid congenital adrenal hyperplasia (of StAR, rare), cholesterol side chain cleavage enzyme deficiency (P450scc, rare) and the like
    .

    The biochemical and clinical manifestations of various types of CAH are complex and diverse, and their differences may overlap
    .

    Even for a certain type of the same type, because of different mutations in the same gene or mutations in the same gene, the degree is different, which may lead to significantly different clinical characteristics
    .

    The clinical manifestation of CAH is a wide spectrum of continuous changes, mainly including sex hormone abnormalities (females ranging from sexual naivety, secondary sexual characteristics dysplasia, mild Kaohsiung to hermaphroditism and fully virilized external genitalia, normal menstruation, menstrual disorders to primary Sexual or secondary amenorrhea; men ranging from fully feminized external genitalia, hermaphroditism, sexual naivety, secondary sexual characteristics dysplasia to precocious puberty), mineralocorticoid abnormalities (from mineralocorticoid not lacking, mild lack to complete lack Low blood pressure, low sodium and high potassium, never increased, slightly increased to significantly increased hypertension, hypokalkaloidosis), cortisol abnormality (never lack, mild lack to complete lack)
    .

    The typical CAH is still easy to diagnose, but compared with the classic CAH, the non-classical CAH (NCAH) enzyme activity is only reduced by 20%-50%, and most of the functions are retained, with mild symptoms, diverse clinical manifestations and lack of specificity.
    It is often hidden in common diseases such as polycystic ovary syndrome (PCOS), acne, hirsutism, menstrual disorders, and infertility, and it is easier to miss diagnosis
    .

    PORD is a rare type of CAH.
    Let's share the data of a case of "Cytochrome P450 Oxidoreductase Deficiency (PORD)" in our hospital's reproductive center due to infertility
    .

    Case data General medical history: SunJS, 2765771, female, 32 years old, 2021.
    6 First visit Chief complaint: 7 years of infertility Present medical history: The patient was married for 7 years, had sex for 2-3 times a month, and was not pregnant without contraception
    .

    Menarche at the age of 12, menopause at the age of 13 for 6 months, normal after taking Chinese medicine treatment, regular menstruation, 4-5/28-30, normal volume, with dysmenorrhea
    .

    Normally, I have fatigue and low blood pressure, my diet is salty, and I feel uncomfortable after drinking a lot of boiled water
    .

    There is no recurring acne and hirsutism
    .

    Past history: No abnormalities in the external genitalia at birth, fainted once after crying at the age of 5, shocked after being beaten at the age of 7, and fainted once due to emotional excitement at the age of 13, with a history of repeated leukopenia; Follicle monitoring was performed in 2018 Luteinized follicle syndrome (LUFS) without rupture for 3 times; surgical treatment of “ovarian chocolate cyst” in Beijing Phoenix Hospital in 2019; history of hepatitis B “small three positives”; history of endometriosis; history of drug allergy , The specifics are unknown
    .

    Family history: healthy parents, non-consanguineous marriages, whether the mother had acne, hirsutism and other Kaohsiung manifestations during pregnancy is unknown; an older brother died of liver disease, the specific cause of which is unknown
    .

    Physical examination: BP115/79mmHg, height 158cm, weight 55kg, BMI22kg/m2, no special physical signs, no deformities on the face and limbs, no acne on the face, black spinous skin, purple skin streaks, hairy (-), normal breast development, lung heart abdomen ( -), normal adult female external genitalia, both lower limbs are not swollen
    .

    Preliminary diagnosis: female infertility diagnosis and treatment after 2021-6-22 menstrual fourth day 2021-7-18 menstrual second day 2021-7-19 menstrual third day Note: due to high progesterone to improve 17-OHP, ACTH, F check CAH
    .

    2021-8-22 Promoting discharge on the 6th day Note: Due to high progesterone, add dexamethasone 0.
    75mg qn
    .

    2021-9-12 Menstrual Day 3 Note: After taking 1/2 tablet of dexamethasone every night, the 17-OHP is significantly lower than before
    .

    After taking 1 tablet of dexamethasone a day, the patient's appetite increased, and her weight gain was obvious.
    She reported that she gained 1 kg a day in the first week and had obvious headaches.
    Afterwards, she reduced the dose to 1/2 tablet daily and her symptoms improved
    .

    Head MR: no abnormal chromosome karyotype: 46, XXCYP21A2 gene screening: no abnormal clinical thinking.
    Patients with 7 years of infertility are expected to undergo IVF reproductive technology in our hospital.
    Early follicular progesterone is found in the perfect routine examination The 17-OHP is slightly high, and the 17-OHP is also slightly high after the endocrinology consultation, and then the CAH is checked
    .

    From the steroid synthesis pathway shown in the figure below, we know that progesterone and 17-OHP are only produced in the ovaries, adrenal glands and testes
    .

    The patient’s non-pregnant state, the early follicular stage progesterone and 17-OHP increased, suggesting that it comes from the adrenal glands, the most common diseases are PCOS, CAH (90%-95% of CAH is 21-OHD), and the patient’s basic ACTH High levels and a significant decrease in progesterone and 17-OHP after taking small doses of dexamethasone also support the diagnosis of CAH
    .

    The 2016 edition of the "Consensus on the Diagnosis and Treatment of Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency" pointed out that elevated 17-OHP is a specific diagnostic indicator and main treatment monitoring indicator for 21-OHD
    .

    According to the basic 17-OHP measured value, it is divided into 3 sections to guide the diagnosis and classification: ①>300nmol/l (10000ng/dl), considered as classic 21-OHD; ②6-300nmol/l (200-10000ng/dl) Consider non-classical; ③<6nmol/l (200ng/dl) does not support CAH or NCAH
    .

    If the diagnosis is clinically similar, ACTH provocation test is required
    .

    The basic value belongs to the conditions of Article ② and ③.
    After the ACTH excitation test, the approximate threshold value of the 17-OHP excitation value is: 17-OHP>300nmol/l (10000ng/dl), it is considered as the classic 21-OHD, After excitation, 30-300nmol/l (1000-10000ng/dl) is considered non-classical, and <30nmol/l (1000ng/dl) excludes 21-OHD
    .

    The 2018 version of the American Endocrine Society guidelines no longer judge the clinical phenotypes of classic and non-classical 21-OHD based on the segment of the 17-OHP measurement value, and the diagnosis process is more concise
    .

    Table ENDO2018 clinical practice guideline 21-OHD diagnosis process.
    The patient's basic 17-OHP is 531.
    01ng/dl (5310.
    1pg/ml).
    ACTH provocation test should be performed according to the diagnosis process, but it cannot be done because there is no ACTH preparation in our hospital
    .

    Non-classical 21-OHD and the more common clinical PCOS have many things in common, including increased androgen levels, insulin resistance, and adrenal hyperresponsiveness
    .

    There was no significant difference between the two types of patients in many indicators such as age, body mass index, waist-to-hip ratio, hirsutism score, and acne incidence
    .

    In view of the high incidence of PCOS, the lack of uniform and specific diagnostic criteria and other factors, the misdiagnosis of NCAH as PCOS has become a more prominent clinical problem
    .

    Chronic hyperandrogenemia of NCAH can also prevent the formation of dominant follicles, change the morphology and function of the ovaries, and present the imaging manifestations of polycystic ovaries
    .

    Studies have shown that at least 40% of NCAH have polycystic ovarian changes, but it is difficult to distinguish from clinical manifestations, so the ACTH stimulation test is particularly important
    .

    The high androgen of PCOS mainly comes from the ovary.
    Due to the increased frequency of GnRH release, the LH rises and the LH/FSH ratio increases, which stimulates the ovaries to secrete too much androgen.
    At the same time, hyperinsulinemia often aggravates this vicious circle.

    .

    The adrenal glands of PCOS patients are in a state of high response, and cortisol and 17-OHP increase simultaneously after stimulation with ACTH, but the blood 17-OHP is generally lower than 16nmol/l, while the increase of cortisol in NCAH patients is significantly lower after ACTH stimulation At 17-OHP, blood 17-OHP is higher than 30nmol/l
    .

    This patient has regular menstrual patterns, no manifestations of Kaohsiung and Kaohsiung, no manifestations of metabolic syndrome such as obesity and hyperinsulinemia, no increase in the LH/FSH ratio, and no polycystic changes in the ovaries.
    None of these clinical features support the diagnosis of PCOS, so it is still considered Possible for NCAH
    .

    In view of the negative genetic screening of 21-OHD, the most common type of CAH, it is recommended that a wider range of genetic testing be performed, and unexpected results will eventually be obtained
    .

    Genetic test results: POR gene compound heterozygous mutation diagnosis of cytochrome P450 oxidoreductase deficiency (PORD) protocol 1.
    Prednisone 2.
    5mg qd2.
    IVF reproductive technology CAH: PORD cytochrome P450 oxidoreductase deficiency (PORD) ) Is a relatively rare category in CAH
    .

    Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that plays a central role in the electron transfer from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to P450 enzymes
    .

    POR plays a key role in the 17,20-lyase reaction of P450c17.
    It interacts with all 57 microsomal P450 enzymes, including P450c21 (21-hydroxylase) and P450c19 (aromatase), as well as many others involved in the liver Enzymes for drug metabolism
    .

    Figure The role of P450 oxidoreductase (POR) in the process of electron transfer to microsomal (type Ⅱ) P450 enzyme.
    Note: NADPH interacts with POR, binds to the endoplasmic reticulum, and transfers a pair of electrons to FAD.
    The change in charge leads to a conformational change.
    , Which allows electrons to pass from FAD to FMN
    .

    After further rearrangement, the FMN domain can interact with the redox binding site of the P450 enzyme (such as P450c17, P450c21, P450c19) to transfer electrons to the active heme prosthetic group of the P450 enzyme, so that the substrate is catalyzed
    .

    The interaction between POR and P450 enzyme is coordinated by the negatively charged acid residues on the surface of the FMN domain of POR and the positively charged basic residues on the binding site of the P450 enzyme redox reaction
    .

    In human P450c17, the allosteric effect of cytochrome b5 and serine phosphorylation of P450c17 promote this interaction
    .

    NADPH, reduced nicotinamide adenine dinucleotide phosphate; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide
    .

    After describing several patients with significant 17-hydroxylase/17,20-lyase (CYP17) and 21-hydroxylase (CYP21) combined deficiencies, the potential role of POR in human steroid synthesis has surfaced
    .

    These patients not only manifested with fuzzy genitalia and abnormal combined steroid production defects, but also manifested with varying degrees of Antley-Bixler syndrome (ABS)-like bone deformities
    .

    ABS is a rare craniosynostosis syndrome, manifested as craniosynostosis, perinatal radial humeral fusion, characteristic facial features and skeletal deformities, such as mid-face dysplasia, short head, prominent forehead, posterior Nostril stenosis, multiple joint contractures, heart malformations, Marfan syndrome, and visceral abnormalities are more pronounced in the urogenital sinus, such as anus and vaginal atresia
    .

    The POR gene is located on chromosome 7q11.
    2 and consists of 15 exons, with a total length of 32.
    9 kb, and encodes a protein of 680 amino acids
    .

    Hundreds of POR gene mutations have been reported, involving missense, frameshift, and splice site mutations, but the mutation sites of this gene are scattered and there are no obvious hot spots
    .

    A287P is the most common mutation in Caucasians, and R457H is the most common mutation in the Japanese population
    .

    All patients carry POR mutations, and they are either partially inactivated or, in the case of major loss-of-function mutations, only show up in a compound heterozygous state
    .

    Homozygous mutations with complete loss of function are likely to be infeasible-this view is supported by the infeasibility of complete deletion of the POR gene in a mouse model
    .

    The first recessively inherited human POR mutation was described in 2004, and a wide range of phenotypes have been described in patients
    .

    At the most serious end of the spectrum is the obscure external genitalia, with or without ABS-like deformities, due to obvious combined defects of CYP17 and CYP21
    .

    Mild defects of POR are also seen in women with a phenotype similar to PCOS and men with mild gonadal dysfunction, sometimes accompanied by mild skeletal features
    .

    Fibroblast growth factor receptor 2 (FGFR2) activating mutations have also been reported to be associated with ABS, but these patients do not have ambiguous genital or steroid production defects
    .

    The overall incidence of POR deficiency has not been determined
    .

    However, within a short period of time after the initial description of the molecular etiology of the disease, many cases of POR deficiency have been reported
    .

    Most patients with POR deficiency have normal electrolyte and glucocorticoid function
    .

    Cortisol deficiency may exist.
    The level of basic glucocorticoid secretion is normal or low, but the response to ACTH stimulation is reduced, the synthesis is insufficient under stress, and even induces adrenal crisis.
    Therefore, glucocorticoid replacement therapy is required
    .

    Some patients have increased mineralocorticoids due to 17-hydroxylase/17,20-lyase deficiency, which may manifest as mild hypertension
    .

    Serum 17-OHP concentration is usually elevated, the response to ACTH stimulation is variable, and sex steroid levels are often lower
    .

    In individuals 46, XY and 46, XX, POR deficiency may be related to the illegibility of external genitalia
    .

    46.
    ​​XY males suffer from androgen deficiency due to the disorder of 17,20-lyase activity in the process of steroid synthesis in fetal mesenchymal cells
    .

    Part of androgenization in 46,XX babies is more common, which may be the result of aromatase activity disorder, because POR is an electron donor for aromatase, and aromatase deficiency can lead to the development of 46,XX fetuses Prenatal androgenization
    .

    As an alternative or in addition, the "backdoor" pathway of androgen biosynthesis has been described in some species, such as the Eugene kangaroo (tammar wallaby)
    .

    The decrease in CYP21A2 activity can cause 17-OHP to accumulate in the fetus and through the "backdoor pathway" [when the fetus is in the mother, 17-OHP can be converted into 17-hydroxy-dihydroprogesterone through 5α-reductase 1 and further produce androsterone, Dihydroandrosterone is finally converted into the most biologically active androgen, dihydrotestosterone, and because this pathway does not belong to the traditional androgen production pathway, it is called the "backdoor pathway"; 5α-reductase 1 is converted after the fetus is born For 5α-reductase 2, the "backdoor pathway" is closed
    .

    ] Converted into active dihydrotestosterone
    .

    At the same time, the decrease of CYP19A1 activity can cause the conversion of androgens to estrogen to be blocked.
    The fetus with chromosome 46, XX may have clitoral hypertrophy, labia fusion, small penis, hypospadias and other external genital abnormalities at birth.
    At the same time, excessive androgen can also It can make maternal masculinization manifestations, such as acne, hirsutism, etc.
    , but it will get better after delivery
    .

    In addition, after the fetus is born, because the "backdoor pathway" is closed and only the classic androgen production pathway is left, the serum androgen level will return to normal or be at a low level, and the clitoris will no longer increase in female children
    .

    Compared with other types of CAH, PORD patients can see male and female external genital malformations, in which girls have obvious virilization of external genitalia, indicating excessive androgen before birth, while boys may show insufficient virilization and varying degrees (from borderline minipenis Severe perineum and hypospadias may occur)
    .

    In this backdoor pathway model system, 17-OHP can be converted into DHT without androstenedione or testosterone as intermediates, which can explain the paradox of fetal virilization but lack of sex hormones after birth
    .

    Emerging data suggests that this approach may also play a role in human development
    .

    The puberty of children with POR deficiency may be different, especially for girls with delayed or disordered puberty
    .

    Any child with skeletal features and hypospadias (46, XY), clitoral enlargement (46, XX), or adolescence that has not progressed should be considered for this diagnosis
    .

    Few patients have been described as having biochemical evidence that appears to be a combined defect of 17-hydroxylase and 21-hydroxylase
    .

    Urine gas chromatography/mass spectrometry analysis showed a typical pattern, including an increase in metabolites of pregnenolone and progesterone, a slight increase in metabolites of corticosterone, an increase in excretion of gestrinolone, and a decrease in androgen metabolites
    .

    The mothers of affected children during pregnancy have low serum estriol levels and have characteristic urine steroid characteristics, so prenatal biochemical diagnosis can be performed
    .

    Only limited analysis of serum steroids may lead to misdiagnosis
    .

    The impaired activity of 17,20-lyase leads to insufficient androgen synthesis, and affected boys are usually born with insufficient virilization
    .

    Most affected girls are born with masculine genitals
    .

    Therefore, patients can show 46, XY or 46, XX DSD, or the male and female external genitalia develop properly
    .

    After birth, virilization does not progress, and the concentration of androgens in the circulation is usually very low
    .

    Some mothers show signs of virilization during the second trimester of pregnancy with an affected child, which usually disappears shortly after birth, further indicating excessive intrauterine androgens
    .

    PORD patients mainly manifested as a disorder of sex hormone synthesis in adulthood, and were mainly characterized by delayed pubertal development
    .

    Male patients may present with small testes, while female patients may present with irregular menstruation, ovarian cysts, and infertility, which need to be differentiated from PCOS and 21-OHD clinically
    .

    This patient presented to the doctor due to infertility and had a history of "ovarian cyst" surgery
    .

    The causes of ovarian cysts in patients with PORD are mainly divided into the following two aspects: ① lack of estrogen leads to increased secretion of follicle-stimulating hormone and luteinizing hormone, which then stimulates ovarian hyperplasia; ② lack of POR causes a decrease in the activity of lanosterol 14α-demethylase (CYP51A1) And cause the reduction of meiosis-promoting sterols, and then cause oocyte meiosis and maturation disorders
    .

    Among the several subtypes of CAH, only PORD will have skeletal deformities, including mid-face hypoplasia, cranial suture fusion, and perinatal radial humeral suture fusion, which in some cases meets the standards of ABS
    .

    At present, the specific mechanism of PORD leading to skeletal deformities is not completely clear, which may be related to the following mechanisms: PORD leads to impaired cholesterol biosynthesis, especially POR-dependent CYP51A1 activity impaired, cholesterol reduction, and Hedge-hog (Hh) expression in chondrocytes The Hh signaling pathway plays an important role in the regulation of embryonic development (growth, morphogenesis) and the process of bone formation
    .

    PURSLEY and other studies have shown that infants delivered by pregnant women who received fluconazole (a known CYP51A1 inhibitor) treatment during pregnancy showed ABS-like skeletal deformities
    .

    This patient has no skeletal abnormalities, suggesting that different types of POR gene mutations may have different effects on related enzyme activities, and the relationship between POR gene mutation types and clinical phenotypes needs further study
    .

    It should be pointed out that patients with PORD may be found in neonatal screening or baseline biochemical examination due to elevated serum 17-OHP levels, and sometimes they may be misdiagnosed as 21-hydroxylase deficiency due to mutations in the CYP21A2 gene
    .

    In summary, PORD is an autosomal recessive genetic disease.
    The complex mutation spectrum of the POR gene leads to various clinical manifestations of patients with PORD, which are easily hidden in common diseases such as PCOS, acne, hirsutism, menstrual disorders, infertility, etc.
    , Which leads to misdiagnosis
    .

    Clinically, if adolescent women with menstrual disorders or amenorrhea, with elevated androgen levels, with or without characteristic skeletal deformities, the possibility of CAH should be considered and differentiated from PCOS and 21-hydroxylase deficiency, and related examinations should be actively improved , And highly suspected PORD patients should undergo genetic testing to confirm the diagnosis, so as to achieve the purpose of early diagnosis, standardized treatment, and prenatal and postnatal care
    .

    10%-30% of CAH women of childbearing age suffer from infertility, and anovulation is the main cause of infertility in CAH women
    .

    Increased adrenal androgens can inhibit the occurrence of follicles and disrupt the normal secretion of gonadotropins.
    In addition, progesterone derived from the adrenal glands can also interfere with the normal menstrual cycle, causing abnormal cervical mucus, affecting sperm penetration and endometrial atrophy.
    Embryo implantation
    .

    This patient had "simple" infertility as the main manifestation, and was eventually diagnosed as a rare type of CAH—PORD.
    The patient had no hyperandrogenism and Kaohsiung manifestations, and no cortisol and mineralocorticoid deficiencies
    .

    However, retrospectively, the patient usually has fatigue and low blood pressure, a history of repeated leukopenia, a salty diet, a feeling of discomfort after drinking a lot of boiled water, and fainting due to mood swings several times in a few hours.
    These unspecific manifestations are actually It indicates the potential adrenal cortex insufficiency, which means that the adrenal cortex hormone secretion is insufficient under stress, and short-term glucocorticoid replacement is needed at that time
    .

    Of course, it is better confirmed by ACTH stimulation test
    .

    In addition, whether the patient’s brother died of liver disease is due to hepatitis or the decrease in CYP450 enzyme activity caused by POR gene mutation.
    After all, the CYP family is the most important drug/toxic metabolizing enzyme, and the liver is its main expressing organ
    .

    The author introduces Dr.
    Ge Zhijuan, Deputy Chief Physician, Master of Obstetrics and Gynecology, Deputy Director of the Reproductive Center of Shuyang County People’s Hospital; Member of the Second Reproductive Medicine Branch of Jiangsu Medical Association, Member of the Reproductive Health Service Professional Committee of Jiangsu Maternal and Child Health Research Association, Maternal and Child of Jiangsu Province Member of the Reproductive Branch of the Health Care Association; engaged in teaching and scientific research in obstetrics and gynecology for more than 20 years
    .

    Presided over a scientific research project of Jiangsu Maternal and Child Health Association, and published many papers in domestic Chinese core journals
    .

    Specializes in the diagnosis and treatment of female infertility, reproductive endocrine diseases and recurrent miscarriage and assisted reproductive technology
    .

    About the author: Dr.
    Zhang Qianjin, deputy chief physician, lecturer, and postgraduate; director of the Department of Endocrinology, Shuyang Hospital Affiliated to Xuzhou Medical University; deputy director of the Endocrinology Branch of the Suqian Medical Association, and deputy director of the Suqian Medical Association of Integrated Traditional Chinese and Western Medicine; for endocrine diseases Especially difficult, rare/rare diseases keep a keen interest, personal public account "endocrine regulator"
    .

    References: [1] Shlomo Melmed,RichardJ.
    Auchus,Allison B.
    Goldfine et al.
    Williams Textbook of Endocrinology 14th Edition, 2019:527-538,867-936.
    [2] Chen Kang ENDO.
    W14th Congenital Adrenal Hyperplasia- 21-hydroxylase deficiency.
    [CK medical science] public account.
    [3] Chinese Medical Association Pediatrics Division of Endocrinology, Genetics and Metabolism.
    Consensus on the diagnosis and treatment of congenital adrenal hyperplasia 21-hydroxylase deficiency[J].
    China The Journal of Pediatrics, 2016,54(8):569-576.
    [4] Speiser Phyllis W, Arlt Wiebke, Auchus Richard J et al.
    Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline.
    [J ] .
    J Clin Endocrinol Metab, 2018, 103: 4043-4088.
    [5] Qi Qi, Hu Honglin, Xu Min, et al.
    A case report of congenital adrenal hyperplasia caused by mutation of cytochrome P450 oxidoreductase gene and literature review[J ].
    Chinese General Practice, 2021,24(30): 3900-3904.
    [6] Ning Guang.
    Improve the diagnosis and treatment of non-classical 21-hydroxylase deficiency[J].
    Chinese Journal of Endocrinology and Metabolism, 2007,23 (5):385-387.
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